Correction of Sickle Cell Disease in Adult Mice by Interference with Fetal Hemoglobin Silencing

被引：268

作者：

Xu, Jian ^{[1
,2
,3
,4
]}

Peng, Cong ^{[1
,2
,3
]}

Sankaran, Vijay G. ^{[1
,2
,3
,7
,8
]}

Shao, Zhen ^{[1
,2
,3
]}

Esrick, Erica B. ^{[1
,2
,3
,5
]}

Chong, Bryan G. ^{[1
,2
,3
]}

Ippolito, Gregory C. ^{[6
]}

Fujiwara, Yuko ^{[1
,2
,3
,4
]}

Ebert, Benjamin L. ^{[5
]}

Tucker, Philip W. ^{[6
]}

Orkin, Stuart H. ^{[1
,2
,3
,4
]}

机构：

[1] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA

[4] Howard Hughes Med Inst, Boston, MA 02115 USA

[5] Harvard Univ, Dana Farber Canc Inst, Brigham & Womens Hosp, Harvard Stem Cell Inst,Med Sch, Boston, MA 02115 USA

[6] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA

[7] Broad Inst, Cambridge, MA 02142 USA

[8] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

来源：

SCIENCE | 2011年 / 334卷 / 6058期

关键词：

MOUSE MODEL; GAMMA-GLOBIN; BCL11A; BETA; HAEMOGLOBIN; THALASSEMIA; FAMILIES; THERAPY;

D O I：

10.1126/science.1211053

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Persistence of human fetal hemoglobin (HbF, alpha(2)gamma(2)) in adults lessens the severity of sickle cell disease (SCD) and the beta-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of gamma-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.

引用

页码：993 / 996

页数：4

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